Overall Summary Abstract Our Center brings together three multidisciplinary Project teams focusing on the biologically critical question: What is the full genetic architecture that determines the hypothalamic control of human reproduction? Using the mendelian human disease model of Isolated GnRH Deficiency (IGD), Project 1 will accelerate its successful novel gene discovery efforts in our existing and fully phenotyped IGD cohort of >2,000 to identify new genes critical for human reproduction as attested to by their creation of IGD when mutated. Using whole exome, whole genome, and RNA sequencing in selected subsets of this cohort such as those: i) sharing a 2nd rare phenotype; ii) with known structural abnormalities; or iii) from multiplex families, we will identify a wide range of coding and non-coding defects in this population. These resulting new ?candidate IGD genes? are then forwarded to Project 3 for in vivo functional confirmation in zebrafish. Project 2 will focus its complex trait genetic expertise on identifying new genetic loci/genes associated with the 3 commonest reproductive disorders in women: PCOS, premature ovarian insufficiency, and hypothalamic amenorrhea. Using genome wide association studies combined with tracking of these conditions with associated genetic loci in several population cohorts where genotypes and phenotypes are already available (cf. Letters of Collaboration), P2 will surface large numbers of new, common, and milder loss of function (LoF) mutations in genes underlying these diseases. As sufficient new loci/genes become apparent, P2 will assemble these new genes into new biology pathways regulating various physiologic and pathologic controls of human reproduction. P3 will validate each of these new candidate genes using a zebrafish bioassay. By then recalling our IGD and population patients harboring these novel mutations to re-phenotype them and thus define the full, unbiased phenotypic spectrum of associated phenotypes, penetrance, varied expressivity, and interactions with other genes associated with each new genes in our Educational/Outreach Core. Collectively, these inter-disciplinary, integrated approaches, techniques, and expertise will provide a deeper understanding of the range of reproductive defects associated with these new genes that are critical for normal human reproduction.